Plan B 0.750 mg

No formal pharmacokinetic studies of the effect of food have been performed. Efficacy is presumed to be independent of the timing of meals since no instruction on timing of dosing relative to meals was provided to the participants in the primary clinical trials supporting the indication.

Use of oral contraceptives can modify the results of laboratory tests. Lab tests should therefore be done prior to dosing or more than 3 days after dosing to avoid misinterpretation of the results. Pathologists should be advised about oral contraceptive therapy when specimens obtained from Pap smears are submitted for examination.

(See below for rifampicin.) No consistent effect has been found in formal pharmacokinetic studies of a number of antibiotics (including ampicillin, clotrimoxazole, tetracycline, the quinolone temafloxacin, and the macrolide clarithromycin) on plasma concentrations of steroids, in particular ethinyl estradiol. It is impossible at the present time to evaluate fully the potential impact of antibiotics on efficacy based on the literature.

There was a marked decrease in the AUC of levonorgestrel following 12 weeks of treatment with phenytoin and carbamazepine (42% and 40%, respectively). In contrast, sodium valproate had no detectable effect. These results are consistent with the known effects of the drugs on liver enzyme induction. A number of reports exist in the literature on oral contraceptive failures in women using certain anticonvulsants, most commonly phenytoin.

Interactions with herbal products have not been established.

Rifampicin is a potent enzyme inducer and, as with anticonvulsant drugs, there is a molecular basis for expecting an interaction with contraceptive steroid efficacy. Oral contraceptive failures, menstrual abnormalities, and low progestin levels have been shown in subjects being treated simultaneously with oral contraceptives and rifampicin.

Paracetamol is metabolized primarily by conjugation with sulfuric and glucuronic acids and hence has the potential for interfering with ethinyl estradiol metabolism. However, a similar effect on levonorgestrel was not shown in the same study.

There are no published drug interaction studies of levonorgestrel. Contraceptive steroids are known to be sensitive to anticonvulsants, griseofulvin, rifampicin, and certain other antibiotics (decreased efficacy) and acetaminophen.

Plan B can be administered at any time during the menstrual cycle.

Two tablets of Plan B (levonorgestrel 0.75 mg) should be taken at the same time, orally, as soon as possible but within 72 hours after unprotected intercourse. The total dosage for one complete regimen of Plan B consists in a single dose of 1.50 mg levonorgestrel.

The patient should be instructed to contact her health care provider if she vomits in the first hour after taking the dose of medication. An additional dose may be administered, based on the judgment of the health care provider. In clinical studies, of the 55 women who vomited as a result of taking Plan B, 40 took a replacement dose. Statistical analysis showed that the replacement dose did not increase efficacy significantly. If vomiting occurs as a result of taking Plan B, it is possible that sufficient quantities of the hormone have been absorbed, as the maximum blood level after oral consumption is reached in about 1.6 hours. If vomiting occurs, for other reasons (such as the flu), or if the pills are visible in the emesis, a replacement dose may be warranted.

The patient should be counselled to abstain of or use an alternative method of contraception (e.g., diaphragm or condom) until the next menstrual cycle. A menstrual period usually begins within 2-3 weeks after medication administration.

acute appendicitis, air in stomach, constipation, polydipsia.

Data were compiled from a number of sources in order to provide an assessment of the post-marketing safety profile of levonorgestrel 0.75 mg tablets; the results yielded very low numbers of adverse events. There were no signals in the reporting that identified any concerns. When the total adverse events were compared to the estimated sales and usage, the percentages were extremely low. The most common adverse events were consistent with those reported in clinical studies and published data.

high platelets counts, low haemoglobin (anaemia hypochromic).

otitis.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

blood in urine, cystitis, ketone positive in urine, urinary protein increased, white blood cells positive in urine.

acne, acne aggravated, chapped lips, rash.

back muscular pain, influenza, light headedness, numbness in lower extremities, migraine NOS, redness arms, redness of the chest, tiredness.

coughing, rhinitis, sinusitis NOS.

blood glucose increased.

corpus luteum cyst or haematoma, ectopic pregnancy termination, late menses, vaginal mycosis.

weeping.

muscle twitching, leg cramps.

acute tonsillitis, otitis, pharyngitis.

Frequency of Adverse Experiences by Body System Reported in ≥1% of Subjects for Emergency Contraception: Subjects in Study 97902

There are in general no serious adverse drug reactions to report following the use of Plan B, either in clinical trials or post-market surveillance. Most commonly observed adverse drug reactions are presented in the following sections.

palpitations.

Plan B has not been studied in this population.

If you determine that a woman is a repeat user of Emergency Contraception (defined as use more than once a month on a regular basis) or that Plan B has been used within the past cycle, you should consider discussing other, more effective contraceptive methods with the woman, as well as encouraging her to see her physician or other health professional for contraceptive counseling services and advise on other methods of contraception and prevention of sexually transmitted infections. Plan B should still be dispensed, if indicated.

Plan B has not been studied in this population.

No data is available.

Plan B is not an abortifacient and should not be taken by pregnant women, as it will not be effective. Studies involving women who have taken combined oral contraceptives containing levonorgestrel inadvertently during early pregnancy do not suggest that these drugs have an adverse effect on the fetus and there is no evidence that Plan B (levonorgestrel 0.75 mg tablets) taken as an emergency contraceptive would have an adverse effect on an established pregnancy. However, there are insufficient data to rule out the possibility of adverse effects on the fetus if Plan B is used after a woman is already pregnant or in cases of method failure.

A pregnancy test is warranted if pregnancy is suspected. Women should be counseled to abstain from sexual intercourse or use an alternative contraceptive method until the onset of their next normal menstrual period. If a normal menstrual period has not occurred within 3 to 4 weeks after Plan B has been used, the woman’s pregnancy status should be confirmed with a pregnancy test at the time of next contact with the health professional. Counseling on routine contraception for future use should be provided as appropriate.

Following a single oral dose of 0.75 mg, levonorgestrel does not appear to be significantly metabolized by the liver. The risks of Plan B to women with a history of liver disease are unknown. Women with a history of liver disease should be given Plan B under medical supervision especially if the method needs to be administered more than once.

No data is available.

Plan B is not an abortifacient. Patients should be advised that Plan B provides no protection against HIV infection (AIDS) and other sexually transmitted diseases.

The use of cyclic combination oral contraceptives containing estrogen and progestin is associated with increased risks of several serious conditions, including thromboembolic and cardiovascular disorders (e.g. thrombophlebitis, pulmonary embolism, cerebrovascular disorders, myocardial ischemia, mesenteric thrombosis, retinal thrombosis), hepatic neoplasia and gallbladder disease. These conditions have not been associated with the routine use of progestin-only oral contraceptives, but whether short-term (single dose) use of high-dose progestin-only contraceptives would accentuate the risk is unknown. Plan B does not contain estrogen. Controlled clinical trials using Plan B and postmarket experience with levonorgestrel for postcoital and emergency contraception have not so far identified any serious adverse events.

Plan B is not recommended for routine use as a contraceptive. The pregnancy rate of Plan B (levonorgestrel 0.75 mg tablets) is calculated for a single use. If Plan B is used on more than one occasion, the cumulative pregnancy rate will be higher.

The effects of Plan B on carbohydrate metabolism are unknown. Some users of progestin-only oral contraceptives experience slight deterioration in glucose tolerance, with increases in plasma insulin; however, women with diabetes mellitus who use progestin-only oral contraceptives do not generally experience changes in their insulin requirements. Nevertheless, diabetic women should be monitored while taking Plan B.

Menstrual bleeding patterns are often irregular among women using progestin-only oral contraceptives and in clinical studies of levonorgestrel for postcoital and emergency contraceptive use. Some women may experience spotting a few days after taking Plan B. At the time of expected menses, approximately 77% of women using Plan B had vaginal bleeding similar to their normal menses, 11-12% bled more than usual and 11% bled less than usual. The majority of women (78%) had their next menstrual period at the expected time or within ±5 days, while only 4.5% had a delay of more than 7 days beyond the anticipated onset of menses. If there is a delay in the onset of menses beyond 1 week, the possibility of pregnancy should be considered.

During the use of Plan B, the onset or exacerbation of migraine or the development of a new pattern that is recurrent, persistent or severe requires evaluation of the cause and may require re-evaluation of a future use of emergency contraceptive pills.

Patients with essential hypertension whose blood pressure is wellcontrolled may be given combined oral contraceptives containing estrogen and progestin, but only under close supervision. Progestin-only oral contraceptives are not contraindicated for such patients.

Ectopic pregnancies account for approximately 2% of reported pregnancies (19.7 per 1000 reported pregnancies). Up to 10% of pregnancies reported in clinical studies of routine use of progestin-only oral contraceptives are ectopic. However, there appears to be no increase in the rate of ectopic pregnancy after use of levonorgestrel for emergency contraception. A history of ectopic pregnancy need not be considered a contraindication to use of this emergency contraceptive method. However, physicians should be alert to the possibility of an ectopic pregnancy in women who become pregnant or complain of lower abdominal pain after taking Plan B.

Administration of combined oral contraceptives and progestin-only contraceptives to breastfeeding women has been reviewed in the literature. Seven studies were reviewed that analyzed the transmission of progestins in breast milk. Data were obtained as early as one week post-partum up to approximately six months post-partum. Very small amounts of progestin have been measured in the milk of breastfeeding mothers who are taking progestin-only contraceptives. Levonorgestrel is transferred from maternal breast milk to infants, with infant plasma levels approximately 40% of those in breast milk and approximately 1% to 6% of maternal plasma. No adverse effects due to progestin-only oral contraceptives have been found on breastfeeding performance, either in the quality or quantity of the milk, or on the health, growth, or development of the infant.

Emergency contraceptives are intended to be used after known or suspected contraceptive failure or unprotected intercourse. They are not effective if a woman is already pregnant. Plan B (levonorgestrel) is believed to act as an emergency contraceptive principally by preventing ovulation or by inhibiting fertilization (by altering tubal transport of sperm and/or ova). It may also prevent implantation (by altering the endometrium). It is not effective once the process of implantation has begun.

Due to the age range of women participating in these studies (19-44 years), and given that the target population for levonorgestrel emergency contraception is comparable, age effects have not been evaluated.

No formal pharmacokinetic studies have been conducted in patients with renal or hepatic impairment. Since the product is administered as a single course of treatment there is no concern about the potential accumulation that might occur with chronic dosing in patients with hepatic or renal impairment.

Summary of Levonorgestrel 0.75 mg Single Dose Tablet Pharmacokinetic Parameter Values by Ethnicity

Following a single oral dosage, levonorgestrel does not appear to be extensively metabolized by the liver. The primary metabolites are 3a,5b- and 3a,5a-tetrahydrolevonorgestrel with 16b-hydroxynorgestrel also identified. Together, these account for less than 10% of parent plasma levels. Urinary metabolites hydroxylated at the 2a and 16b positions have also been identified. Small amounts of the metabolites are present in plasma as sulfate and glucuronide conjugates.

The absolute bioavailability of Plan B in humans has not been specifically investigated. However, levonorgestrel is reported in the literature to be rapidly and completely absorbed following oral administration and does not undergo first pass metabolism.

One study, also provided results for seven-day dosing of six healthy young women. Serum levels on Day 7 were found to be somewhat lower than Day 1 levels (mean C_max value of 9.0 ng/mL for Day 1; 5.3 ng/mL mean C_max for Day 7 corrected values), and a longer half-life was reported (mean 12.6 hours on Day 7). Steady state was obtained on the fourth day, with no unanticipated accumulation.

Orally administered levonorgestrel is found in breast milk at levels approximating a plasma/milk ratio of 100:15.